The field of the invention is aryl hydrocarbon receptor (AHR) ligands and their use.
Kynurenine is a tryptophan metabolite generated by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3,-dioxygenase (TDO). The cellular levels of kynurenine and its downstream metabolites play crucial roles in regulating the immune system, vascular biology and neurological function (Rudzite, Sileniece et al. 1991, Stone and Darlington 2002, Polyzos and Ketelhuth 2015, Jasiewicz, Moniuszko et al. 2016). Disorders of kynurenine metabolism are associated with a variety of human health issues including cancer, hypertension, chronic inflammation, and neurodegenerative disorders (Stone and Darlington 2002, Oxenkrug 2010, Changsirivathanathamrong, Wang et al. 2011). A number of recent studies have suggested a link between the physiological effects of kynurenine and the aryl hydrocarbon receptor (AHR) (Mezrich, Fechner et al. 2010, Bessede, Gargaro et al. 2014). The AHR is a PAS (PER, ARNT, SIM) family transcriptional factor that is essential for development and normal function of vascular and immune systems (Savouret, Berdeaux et al. 2003, Korashy and El-Kadi 2006, Esser, Rannug et al. 2009, Stevens, Mezrich et al. 2009). In support of this relationship are the numerous observation that kynurenine levels influence a variety of immune responses in an AHR dependent manner (Opitz, Litzenburger et al. 2011, Mezrich, Fechner et al. 2010, Nguyen, Kimura et al. 2010). The underlying mechanistic role of the AHR in kynurenine action is currently uncertain. Although it has been shown that kynurenine is a receptor activator, its structure does not conform to many of the rules that correlate with high affinity binding to the AHR (Fig. s1) (Procopio, Lahm et al. 2002, Bisson, Koch et al. 2009, Pandini, Soshilov et al. 2009, Xing, Nukaya et al. 2012).
Like kynurenine, many cellular metabolites that activate the AHR are derived from tryptophan. For example, exposure to UV radiation in the skin converts tryptophan to 6-formylindolo [3,2-b] carbazole (FICZ) (Rannug, Rannug et al. 1987, Helferich and Denison 1991, Rannug, Rannug et al. 1995), stomach acid converts dietary indole-3-carbinol to indolo [3,3b] carbazole (ICZ), the enzyme d-amino acid oxidase (DAAO) converts tryptophan to indole 3-pyruvic acid, and gut microbiota generate tryptophan derived AHR activators that are crucial for curtailing inflammatory bowel disease and central nervous system inflammation (Zelante, Iannitti et al. 2013, Hubbard, Murray et al. 2015, Lamas, Richard et al. 2016, Rothhammer, Mascanfroni et al. 2016). In addition to endogenous ligands, the AHR also responds to numerous xenobiotic ligands to influence a wide variety of toxicological, immunological, and cardiovascular endpoints (McIntosh, Hogenesch et al. 2010). Knowledge of AHR pharmacology has arisen from studying xenobiotic agonists like the halogenated dibenzo-p-dioxins (e.g. 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), and polycyclic aromatic hydrocarbons (e.g. benzo[a]pyrene, BaP) (Procopio, Lahm et al. 2002, Bisson, Koch et al. 2009, Pandini, Soshilov et al. 2009, Xing, Nukaya et al. 2012). These studies show that AHR prefers elongated planar compounds with large lateral extension and small medial extension with specific medial H-bond potential (FIG. 6). Thousands of xenobiotic compounds and cellular metabolites with diverse shape and chemical properties have been reported to bind AHR (Schmidt and Bradfield 1996, Nguyen and Bradfield 2008). While a majority of AHR ligands have an overall elongated planar shape, some ligands barely have any AHR ligand structural signatures. Kynurenine is one such ligand that is much smaller, polar, and irregular in shape (FIG. 6). Using homology models of AHR-LBD bound to TCDD and BaP, we previously identified key structural signatures for AHR-binding that differentially affect the efficacy of different ligands, and flexible structural elements that are essential for tolerating diverse ligands (Xing, Nukaya et al. 2012). A flexible extended loop of AHR, named “belt”, is longer and more flexible than other PAS family transcription factors, underlying the unique ability of AHR to respond to diverse ligands.
There is a need in the art to further understand what molecules play a part in AHR binding and signaling and the identification of novel compounds that can activate the AHR pathway.